Various approaches to the production of reversibly gelling compositions have been developed over the years. Principal efforts have been devoted to the development of gelatinous drug delivery systems for topical and subcutaneous applications and, more recently, for the administration of ophthalmic drugs to the eye. In general, sustained release drug delivery systems incorporate pharmaceutical agents in solid or semi-solid vehicles which are applied to or implanted under the skin of a patient by medical personnel. However, unlike conventional drug delivery systems, ocular drug delivery systems also must address the additional problem of drug loss through the lacrimal drainage system as well as the needs of patient comfort and ease of administration. Additionally, pharmaceutical drugs have their maximum bioavailability when the drugs are delivered in soluble form. Thus, solid or semi-solid drug delivery systems carrying pharmaceutical drugs having little or no water solubility have the disadvantage of a low bioavailability of the drugs they deliver.
Early approaches to the solution of these problems, as exemplified by ocular drug delivery systems, utilized semi-solid ointments or gels applied directly to the conjunctiva or cul-de-sac of the eye to retain the pharmaceutical agents contained therein on the ocular surface against such physiological factors as tear turnover, tear drainage, blinking, and other mechanical losses. For example, U.S. Pat. Nos. 3,944,427 and 3,700,451 disclose gelatinous drug delivery compositions containing agar, xanthine gum, and carob gum in liquid mediums in order to enhance their residence time upon the skin or mucosae and the resultant bioavailability of the medicinal products contained therein. Similarly, European Patent Application No. 0 300 888 A1, filed Jul. 18, 1988, recently disclosed the use of rhamsan gum to thicken ophthalmic compositions for droppable and topical application.
While the majority of such prior art drug delivery vehicles were aqueous based, this created a problem for the delivery of water insoluble pharmaceutical compounds. Accordingly when formulated to deliver water insoluble drugs these prior art ointments and gels generally included low molecular weight alcohols or similar compounds which dissolved the water insoluble drug into a miscible form to produce an homogeneous system.
Though effective at increasing drug retention times, lack of patient acceptability remains a significant drawback to the use of such known drug delivery compositions in the eye. Many patients experience difficulty in applying the appropriate amount of such compounds to the eye and resist the unpleasant side effects of eyelid crusting and vision blurring. As a result, these compositions may only be suitable for use in the evening or during non-active hours. Additionally, semi-solid and gelatinous drug delivery systems which incorporate non-aqueous solvents such as low molecular weight alcohols for delivering water insoluble drugs are generally irritating to ocular and other sensitive tissues. This irritation generally is manifested in the form of stinging upon administration of the drug delivery system and excessive tearing when administered to the eye.
A known alternative drug delivery approach directed at solving the problems of eyelid crusting and vision blurring caused by applying viscous gel delivery vehicles is the use of a formulation which is liquid at room temperature but which forms a semi-solid when warmed to body temperature. Such a thermally triggered system is disclosed in U.S. Pat. No. 4,474,751, where an aqueous drug delivery system that forms a semi-solid "gel" at body temperature is formed from proprietary polymers known as "Tetronic.RTM." polyols. Generally speaking, these compositions are formed from approximately 10% to 50% of the specific polymers in an aqueous base. By adjusting the pH of these drug delivery systems through the addition of buffering agents, the gelling transition temperature can be raised to physiological temperatures on the order of 35.degree. C. Similar drug delivery systems which can be injected subcutaneously or intramuscularly are disclosed in U.S. Pat. No. 4,474,752. These compounds also contain from 10% to 50% by weight Tetronic.RTM. polymers and gel at temperatures from about 30.degree. to 10.degree. C.
A similar thermal setting gel drug delivery system also is described in U.S. Pat. No. 4,188,373, utilizing "Pluronic.RTM. polyols" as the thermally gelling polymer. Adjusting the concentration of the polymer gives the desired "sol-gel" transition temperature to the composition. However, producing a compound which sets at physiologically useful temperature ranges limits the available viscosity of this gelled product.
Alternatively, it also has been proposed to utilize formulations which gel in response to changes in pH as drug delivery vehicles. By carefully controlling the pH of such mixtures, a solution which forms a gel upon mixing with aqueous tear fluid could theoretically be produced. However, it is believed that the relatively high buffering capacity of such pH responsive compositions can lead to slow gelling, irritation and discomfort when used in patient eyes.
Though generally successful at achieving increased drug retention times, it is known that the relatively high polymer concentrations required by known prior art formulations undesirably increases both the buffering capacity and the amount of thermal energy necessary to induce gelation of the compounds. This may lead to irritation and discomfort when these formulations are used on sensitive tissues such as in the eye. What is more, the high prior art polymer concentrations also contribute to unacceptably high product costs and generally slow the gelling process as well. This latter drawback may lead to migration of the compounds from the site of application or injection.
Additionally, because these known gelling systems are water based and utilize water soluble polymers, their use precludes delivering water insoluble drugs in a soluble form. Thus, the bioavailability of water insoluble drugs delivered from these gelling systems is substantially decreased and their effectiveness is correspondingly decreased.
Accordingly, it is a principal object of the present invention to provide reversibly gelling polymer compositions having significantly lower polymer concentrations than those previously attainable by the prior art. These lower concentrations reduce both the buffering and thermal capacities of the solutions to ensure their rapid and complete transition from liquid to gel upon application to physiological systems such as through an oral dosage, drop instillation to the surface of the eye, or through injection to an injectable drug depot.
It is a further object of the present invention to provide reversibly gelling compositions which can be utilized as drug delivery vehicles or wetting solutions that can be administered easily by a patient in the form of a freely flowing liquid or drops which gel immediately upon administration with minimal side effects. This provides the added benefits of ready patient control of drug dosage and improved patient acceptability.
It is a further object of the present invention to provide oral dosage, drop-instillable or injectable drug delivery vehicles suitable for delivering oil soluble drugs.
It is a further object of the present invention to provide reversibly gelling polymer compositions which can be utilized to deliver oil soluble drugs while maintaining a high degree of drug bioavailability and which prolong drug contact time for sustained drug release.